chr17-43097289-C-A
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3
The NM_007294.4(BRCA1):c.548G>T(p.Gly183Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,746 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G183E) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460746Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726700 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
The missense variant c.548G>T (p.Gly183Val) in BRCA1 has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). The p.Gly183Val variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Gly at position 183 is changed to a Val changing protein sequence and it might alter its composition and physio-chemical properties. The amino acid change p.Gly183Val in BRCA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Hereditary cancer-predisposing syndrome Uncertain:2
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The p.G183V variant (also known as c.548G>T) is located in coding exon 7 of the BRCA1 gene. The glycine at codon 183 is replaced by valine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 7. This alteration has been reported as a variant of unknown significance in a cohort of 67 patients with unilateral hormone-dependent breast cancer and positive family history (Concolino P et al. Int J Mol Sci, 2019 Jul;20:). RNA studies have demonstrated that this alteration results in an a splice defect involving exons excluded from naturally occurring transcripts; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Uncertain:1
Variant summary: BRCA1 c.548G>T (p.Gly183Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250814 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.548G>T has been reported in the literature in at-least one female individual affected with Unilateral Breast, whose father was also a carrier and was diagnosed with Breast Cancer at age of 78 years-old (example, Concolino_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31336956). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with breast cancer (PMID: 31336956). ClinVar contains an entry for this variant (Variation ID: 441376). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 183 of the BRCA1 protein (p.Gly183Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at